Antiepileptic drug combinations--have newer agents altered clinical outcomes?

In 2000, 332 (20.5%) of 1617 patients registered with the Western Infirmary Epilepsy Unit required antiepileptic drug (AED) polytherapy to remain seizure-free for at least 1 year. The analysis was repeated 10 years later. Of 2379 seizure-free patients, 20.4% (n=486 - 254 women, 232 men, aged 18-95 years [median age 49 years]) were receiving combination therapy. Two AEDs were taken by 395 (81.3%) patients in 2010, and by 287 (86.4%) in 2000. Sodium valproate with lamotrigine was the commonest of 64 successful pairings. As a combination, mean daily doses of both AEDs were lower (n=96; sodium valproate 1200 mg, lamotrigine 155 mg) than when sodium valproate was taken with carbamazepine or levetiracetam (n=42; 1621 mg; p<0.001), and lamotrigine was combined with topiramate or levetiracetam (n=33; 430 mg; p<0.001), suggesting possible synergism. In 2010, a higher percentage of patients (n=85) remained seizure-free on 3 AEDs (17.5% in 2010, 12.7% in 2000) in 57 separate regimens. Only 0.9% (n=3) of patients in 2000, and 1.2% (n=6) in 2010 responded to 4 AEDs. Levetiracetam (n=109; 10.2%) and topiramate (n=81; 7.6%) were the newer agents most commonly represented in successful combinations. These data tend to imply that drug substitution rather than addition has largely led to these marginally improved results. In the last decade, when used as adjunctive therapies, newer agents appear not to have impacted substantially on the likelihood of producing seizure freedom. An alternative approach to AED development may be required to change this disappointing scenario.